DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2

Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15091-6. doi: 10.1073/pnas.0607260103. Epub 2006 Oct 2.

Abstract

DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Antioxidants / physiology
  • Cell Line, Tumor
  • Embryo, Mammalian
  • Fibroblasts / chemistry
  • Fibroblasts / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Kelch-Like ECH-Associated Protein 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / metabolism*
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / physiology*
  • Parkinson Disease / etiology
  • Parkinson Disease / metabolism*
  • Peroxiredoxins
  • Protein Deglycase DJ-1
  • Ubiquitin / metabolism

Substances

  • Antioxidants
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Neoplasm Proteins
  • Nfe2l2 protein, mouse
  • Oncogene Proteins
  • Ubiquitin
  • Peroxiredoxins
  • PARK7 protein, human
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1

Associated data

  • GEO/GSE5519